P1/2, N=42, Recruiting, Beijing Biotech

Background: Claudin 18.2 (CLDN18.2) has become a clinically relevant therapeutic target in gastric adenocarcinoma (GC), with zolbetuximab now approved for use in CLDN18.2-positive, HER2-negative advanced disease... CLDN18.2 shows excellent intratumoral reproducibility and a stable biological profile in GC, supporting its diagnostic reliability in biopsies and value as a predictive biomarker. A subset with extreme expression demonstrated aggressive features, suggesting a potential "claudin-driven" phenotype requiring further study.

Following multidisciplinary evaluation, irinotecan combined with zolbetuximab was initiated on the basis of individualized adjustment of the hemodialysis schedule. The regimen was well tolerated, associated with stabilization of renal function, and resulted in a marked decline in serum CA19-9 accompanied by a significant shrinkage of peritoneal metastatic lesions on CT imaging, with sustained disease control during treatment. This case highlights that in patients with advanced gastric cancer undergoing hemodialysis, CLDN18.2-targeted therapy combined with chemotherapy may be feasible and safe with close laboratory monitoring and individualized dialysis management and may serve as a valuable reference for personalized treatment in gastric cancer complicated by renal failure.

Zolbetuximab was launched in June 2024 as an anticancer drug useful for patients with CLDN18.2 positive and HER2 negative curatively unresectable advanced or recurrent gastric cancer. The mechanism and response to side effects such as hypoalbuminemia are still unclear, and more cases need to be accumulated.

Zolbetuximab is an anti-claudin18.2 (CLDN18.2) antibody, and the addition of zolbetuximab in combination with fluoropyrimidine and oxaliplatin as a first-line treatment for CLDN18.2-positive and HER2-negative gastric or gastroesophageal junction adenocarcinoma has been shown to improve survival. The secondary endpoints are the time to treatment failure, progression-free survival, overall survival, response rate, incidence of adverse events, and incidence of Grade 3 or higher adverse events. The results will be used to evaluate the feasibility of the treatment and are expected to be used to evaluate whether future trials can be conducted.

The recent approval by the US Food and Drug Administration (FDA) of the anti-CLDN18.2 monoclonal antibody zolbetuximab marks a significant advancement in the management of locally advanced, unresectable, or metastatic HER2-negative, CLDN18.2-positive G/GEJ adenocarcinoma...Careful selection and evaluation of tumor samples, particularly in small biopsies or cytology specimens, are essential to ensure accurate assessment. Standardization of all aspects of CLDN18.2 immunohistochemistry, from specimen preparation to interpretation, is necessary to achieve accurate, reproducible, and clinically meaningful results that guide therapeutic decisions for patients with G/GEJ and pancreatobiliary cancers.

Despite assay variability, even under stringent clinical trial criteria, a meaningful subset of patients may qualify for CLDN18.2-targeted therapy. These findings highlight the need for standardized testing and further clinical evaluation of CLDN18.2-directed strategies in PDAC.

In Japanese patients, zolbetuximab plus chemotherapy improved PFS versus placebo plus chemotherapy and showed a numerical improvement in OS. These results support zolbetuximab plus chemotherapy as a potential new standard-of-care first-line option for Japanese patients with CLDN18.2-positive, HER2-negative, LA unresectable or metastatic gastric or GEJ adenocarcinoma.

However, despite the development of new drugs and the approval of zolbetuximab, there are significant challenges to be addressed, such as intratumoural heterogeneity, sampling bias, and the absence of assay standardization with thresholds suitable for the modality. This review synthesizes the biology and clinical significance of claudins-particularly CLDN18.2 and CLDN6-, highlighting their potential as biomarkers for guiding precision medicine and future development of novel therapeutic agents in gastric cancer patients.

P1, N=398, Recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: May 2027 --> May 2028 | Trial primary completion date: Nov 2026 --> May 2028

The approved antibody zolbetuximab requires higher expression levels (≥75% of tumor cells with 2-3+ membranous staining), yet broader thresholds are increasingly explored...Broadening the threshold for positivity identified nearly three-quarters of patients as CLDN18.2 positive, underscoring the impact of selection cut points on trial eligibility. These findings highlight the potential to expand patient access to CLDN18.2-targeted therapies using lower thresholds.

Specimen type (biopsy or surgical resection) had no apparent impact on treatment outcomes. Within the approved CLDN18-positive threshold, the semiquantitative staining proportion showed no detectable differences in the efficacy or safety of zolbetuximab plus chemotherapy.